Thyroid hormone receptor-α regulates autophagy, mitochondrial biogenesis, and fatty acid utilization in skeletal muscle

[helvella]

One of the many pieces missing from the jigsaw of thyroid is what happens to thyroid hormone inside cells. Medicine has generally ignored the question and just asserted that our cells need thyroid hormone - if they get even that far!

Understanding the fine detail of what it does, and not just in generic "cells" but in each and every type of cell in all our varied tissue types, should be of great benefit. In time, it might well be able to explain many of the multitude of symptoms.

Another welcome step:

Endocrinology

. 2021 Jun 4;bqab112.

doi: 10.1210/endocr/bqab112. Online ahead of print.

Thyroid hormone receptor-α regulates autophagy, mitochondrial biogenesis, and fatty acid utilization in skeletal muscle

Jin Zhou 1 , Karine Gauthier 2 , Jia Pei Ho 1 , Andrea Lim 1 , Xu-Guang Zhu 3 , Cho Rong Han 3 , Rohit Anthony Sinha 4 , Sheue-Yann Cheng 3 , Paul Michael Yen 1 5 6

• PMID: 34086893

• DOI: 10.1210/endocr/bqab112

Abstract

Skeletal muscle (SM) weakness occurs in hypothyroidism and resistance to thyroid hormone alpha (RTHα) syndrome. However, the cell signaling and molecular mechanism(s) underlying muscle weakness under these conditions is not well understood. We thus examined the role of thyroid hormone receptor alpha (TRα), the predominant TR isoform in SM, on autophagy, mitochondrial biogenesis and metabolism to demonstrate the molecular mechanism(s) underlying muscle weakness in these two conditions. Two genetic mouse models, TRα1 PV/+ mice which expresses mutant Thra1PV gene ubiquitously, and SM-TRα1 L400R/+ mice, which expresses TRα1 L400R in a muscle-specific manner, were used in this study. Gastrocnemius muscle from TRα1 PV/+, SM-TRα1 L400R/+, and their control mice was harvested for analyses. We demonstrated that loss of TRα1 signaling in gastrocnemius muscle from both the genetic mouse models led to decreased autophagy as evidenced by accumulation of p62 and decreased expression of lysosomal markers (LAMP1, and LAMP2) and lysosomal proteases (cathepsin B and cathepsin D). The expression of PGC1α, TFAM, and ERRα, key factors contributing to mitochondrial biogenesis as well as mitochondrial proteins were decreased, suggesting that there was reduced mitochondrial biogenesis due to the expression of mutant TRα1. Transcriptomic and metabolomic analyses of SM suggested that lipid catabolism was impaired, and was associated with decreased acylcarnitines and tricarboxylic acid cycle (TCA cycle) intermediates in the SM from the mouse line expressing SM-specific mutant TRα1. Our results provide new insight into TRα1-mediated cell signaling, molecular, and metabolic changes that occur in SM when TR action is impaired.

Keywords: TRα1 mutation; autophagy; lipid metabolism; mitochondrial function; muscle.

pubmed.ncbi.nlm.nih.gov/340...

[FancyPants54]

OK, that's probably really interesting. But any chance of some sort of version that makes sense to those of us without scientific backgrounds. What does it mean to us? I'm not bad at reading these sorts of things in some cases, but this is way beyond me.

[helvella Administrator in reply to FancyPants54]

Very fair point!

Insufficient thyroid hormone impairs the ability of our smooth muscle tissue to turnover cells - replacing damaged ones by pristine new ones.

Also, impairs mitochondrial biogenesis which results in lower effective mitochondrial activity.

And, for lipid catabolism, have a look here: en.wikipedia.org/wiki/Lipid...

(Don't think for one moment that I understand it all - I don't. It is more that it represents progress in understanding by those who can understand! )

[FancyPants54 in reply to helvella]

Thank you. That helps enormously. I'll follow the link after I reply. This is exactly as the way that the muscles in my legs feel. Lower mitochondrial activity and poor muscle repair. My legs hurt all the time.

[FancyPants54 in reply to FancyPants54]

Yes, that lipid description fits too.

[twizzle303 in reply to FancyPants54]

Mine too 😒

[jgelliss in reply to helvella]

Thank you Helvella. This certainly confirms what many of us with muscle discomforts and pain how much thyroids play a roll with it and more. Now if only Dr would read this and understand it too. Maybe thyroid patients would benefit too. Great job Helvella.

[Serendipitious in reply to helvella]

helvella,

Great article, thank you. but this hypothesis was only demonstrated in mouse experiments?

It also tells me that we would need to work harder to maintain mitochondrial biogenesis and autophagy. So things like good sleep, hard for many of us as it is.

[helvella Administrator in reply to Serendipitious]

Everything seems to be in mice, rats, zebrafish, etc.!

We certainly need to bear that in mind whenever we read papers as there are differences that are important. However, thyroid hormone is common to all animals with backbones (possibly others, but the evolutionary distance grows and differences are more likely very important).

We might need to work harder, but maybe we can't achieve? That is, however much work our bodies put in to try to address issues, they simply can't without adequate thyroid hormone.

[asiatic]

I agree with Fancypants. What does it mean. I am in awe of the scientists who do this research and glad helvella brings it to our attention - as she says another piece in the jigsaw and a reminder of just how complex thyroid issues can be.

[Gingernut44 in reply to asiatic]

By the way, she is a he 😀

[asiatic in reply to Gingernut44]

Apologies to helvella. I was probably influenced by the ella suffix and helvella is a mushroom which I suppose is male and female 😱

[helvella Administrator in reply to asiatic]

Fungi can have up to thousands of genders/sexes!

[asiatic in reply to helvella]

I see the fungi is called helvella confusa......no wonder it's confused 😂

[helvella Administrator in reply to asiatic]

It was Crispa that was in my mind - but any of the species are just as valid.

first-nature.com/fungi/helv...

[tattybogle]

Nice find Helvella

According to Wikipedia....Thyroid hormone receptor alpha (TR-alpha).....allegedly looks like this....

......so no wonder it's so blummin hard to understand

[helvella Administrator in reply to tattybogle]

Did someone use this as the basis for a Pride flag?

[tattybogle in reply to helvella]

dunno.. but i used to be able to make something just like that by twiddling the telephone wire while gossiping...

[DippyDame in reply to tattybogle]

Just imagining all that twisted stuff inside my cells...explains why the receptors are playing up....well maybe!!That's alpha investigated, now for beta ....and, perchance, thyroid hormone resistance further investigated

Must read the paper now.

[helvella Administrator in reply to DippyDame]

Not yet available!

[DippyDame in reply to helvella]

I meant the paper you posted above...dictionary to hand!

. Probably got a long wait for further research, but things are beginning to move...slowly! Now we need the medics to, "sit up and pay attention at the back".

[TSH110 in reply to tattybogle]

Just a TR alpha conversation rattling on the line 🤣🤣🤣

[tattybogle in reply to TSH110]

......rattling along the line till something goes wrong with the curvy rails...

Is this what thyroid hormone resistance looks like ?

[DippyDame in reply to tattybogle]

Certainly feels like it!!

[TSH110 in reply to tattybogle]

Certainly feels that way!

[Gingernut44 in reply to tattybogle]

I’m darn sure that is old telephone cable 😀

[TSH110 in reply to tattybogle]

Mind blowing isn’t it?!

[DippyDame]

Great find helvella....thank you!

[Tythrop]

Is does anyone have an idiot-proof translation of this? As it looks interesting and I'd like to understand it.. Diogenese?